) The overall goal of this NCDDG application is to design, synthesize and evaluate novel anticancer drugs based on inhibition of the enzyme, protein geranylgeranyltransferase I (PGGTase I). PGGTase I is an important anti-cancer drug target because substrates for PGGTase I such as RhoA, Rac1, Cdc42, R-Ras and TC-21 promote tumorigenesis and/or metastasis. Furthermore, RhoA, Rac1 and Cdc42 are also required for the transformation of Ras, an oncoprotein involved in 30% of human cancers. Finally, when human cancer cells are treated with farnesyltransferase (FTase) inhibitors, K-Ras and N-Ras become geranylgeranylated by PGGTase I. The hypothesis to be tested is that inhibition of PGGTase I will result in abrogation of tumor growth. To explore this hypothesis we will use a multidisciplinary approach consisting of three distinct but interdependent and complementary programs. Program #1 will design and synthesize peptidomimetics, transition state bisubstrate analogs and mechanism-based inhibitors of PGGTase I. Program #2 will perform structure activity relationship studies on these compounds to determine the requirements for selective inhibition of PGGTase I over the closely related enzymes PGGTase II and FTase in vitro and in whole cells. Program #2 will determine the ability of PGGTase I inhibitors to inhibit DNA synthesis, block cell cycle and promote apoptosis. Program #3 will determine the effects of the compounds on RhoA, Rac1, Cdc42, R-Ras and TC-21 oncogenic signaling, malignant transformation and invasion. Both Program #2 and 3 will address selectivity issues by using murine fibroblasts and human epithelial cells transformed with H-, K- and N-Ras, Src, Raf, EGFR and ErbB2. Feedback from Programs #2 and 3 will be used by Program #1 for lead optimization for second and third generation leads. The best compounds to emerge from these combined studies will then be evaluated by Program #2 for their ability to block the growth of tumors using a nude mouse xenograft model. Here the above transformed cells as well as human tumors with H-, N- or K-Ras mutations and tumors overexpressing Ras, ErbB2 or EGFR will be used. Future plans include advanced preclinical and clinical studies with our industrial and clinical partners. The work described in this NCDDG will enhance our understanding of the mechanism of action of GGTase I inhibitors, and ultimately result in novel anticancer drugs that will broaden the spectrum of human tumors that can be treated successfully.
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